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Snail-Induced Down-Regulation of Np63 Acquires Invasive Phenotype of Human Squamous Cell Carcinoma

Department of Oral and Maxillofacial Surgery, Division of Cervico-Gnathostomatology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan

Requests for reprints: Koichiro Higashikawa, Department of Oral and Maxillofacial Surgery, Division of Cervico-Gnathostomatology, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan. Phone: 81-82-257-5673; Fax: 81-82-257-5671; E-mail: khigashi{at}hiroshima-u.ac.jp.

p63 is a member of the p53 family and regulates crucial events in the formation of epithelial structures, but the role of p63 in tumor is unclear. We found that Snail-induced epithelial-to-mesenchymal transition (EMT) is accompanied by down-regulation of p63 in human squamous cell carcinomas (SCC). Np63 is the predominantly expressed p63 isoform in SCC cells. Np63 promoter activity required a CAAT/enhancer binding protein (C/EBP) binding element and was reduced remarkably by Snail. Down-regulation of Np63 and reduction of C/EBP were observed in EMT phenotype cells, which exhibited invasive activity in vitro. p63 knockdown in cells enhanced invasive activity in the presence of E-cadherin. Conversely, forced expression of Np63 blocked invasive activity of cells with the EMT phenotype. These findings indicate that Snail down-regulates Np63, leading to acquisition of the invasive phenotype by SCC. The invasive activity caused by down-regulation of Np63 does not require down-regulation of E-cadherin. [Cancer Res 2007;67(19):9207–13]

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